1. Field of the Invention
The present invention relates to renin inhibitors, more particularly to pentapeptide substrate analogues of renin, and their use in the treatment of hypertension.
2. Description of the Prior Art
Renin is an acid protease which cleaves the circulating protein angiotensinogen to yield the decapeptide angiotensin I. This is converted into angiotensin II, which controls blood pressure in animals by mechanisms which include constriction of the vascular smooth muscle and regulation of salt and water balance. Angiotensin II is known to be involved in renovascular hypertension, and a role is postulated for this substance in the etiology of essential hypertension. A clinically useful renin inhibitor would have therapeutic relevance for the treatment of these conditions.
There are four classes of compounds which specifically prevent the production of angiotensin by renin. First, antibodies which bind renin can specifically inhibit the enzyme. The use of such antibodies has been reported to lower blood pressure in primates.
The second approach is to use one of the pepstatins, which are low molecular weight protease inhibitors obtained from the culture medium of Streptomyces. (See for example Gross et al, Science 175: 656 (1971), Miller et al, Biochem. Pharmacol. 21, 2941-2944 (1972), and Aoyagi et al, J. Antibiot. 25: 689-694 (1972)). More tractable analogues of pepstatin with greater solubility have been reported (Eid et al, Biochem. J. 197(2): 465-471, (1981), Miyazaki et al, Japan J. Pharmacol. 28: 171-174 (1978)). The data indicate reversal of renin dependent hypertension in the rat and dog with these analogues.
A third approach involves the use of small peptides based on the sequence of angiotensinogen (Kokubo et al, Biochem. Pharm. 22: 3217-3223 (1973)). Poulsen et al (Biochemistry 12: 3877-3882 (1973)) showed that the inhibitory constant for a representative member of the series was about three orders of magnitude greater than for longer inhibitors (such as, e.g. those developed by Burton et al (Proc. Nat. Acad. Sci. USA, 77: 5476-5479 (1980)). Other short inhibitors in which the alpha amino group is replaced by a hydroxyl group have been reported.
Burton et al (Proc. Nat. Acad. Sci., supra) have reported the use of longer substrate analogues for the inhibition of renin in primates. The Renin Inhibitory Peptide (RIP, U.S. Pat. No. 4,269,827, herein fully incorporated by reference), is effective in inhibiting renin in primates. Paiva et al (Oliveira et al, Proc. 7th Amer. Pept. Symp., Pierce Chem Co., Rockford, Ill. 1982, 435-438) have prepared constrained analogues of RIP which are moderately active in vitro but have not been tested in vivo.
Research by Skeggs et al (J. Exp. Med. 128: 13-34 (1968)) indicates that short substrates do not effectively inhibit renin. Poulsen et al (Biochem. 12: 3877-3882 (1973)), for example, have reported that the tetrapeptide Leu-Leu-Val-TyrH.sub.2 has an inhibitory constant (K.sub.I) of 1020 micromolar at pH 7.4. Johnson (J. Med. Chem. 23: 666-669 (1980)) found a similar K.sub.I for the tetrapeptide Leu-Leu-Val-Phe-OCH.sub.3 at pH 7.0. These peptides are about 0.2% as effective as RIP in preventing the formation of angiotensin I by renin.
One particular modification of interest to those of skill in this art would be to develop peptides which are orally active. Modification of RIP, for example, to yield an orally active renin inhibitor would require both a reduction in the size of the inhibitor and an increase in lipophilicity. In addition, an acceptable peptide must be made resistant to digestion by proteolytic enzymes of the gastrointestinal tract. These objectives must be accomplished without markedly diminishing inhibitory potency.
A need therefore continues to exist for inhibitors of renin useful for treatment of hypertension, especially renin-dependent hypertension.